The global burden of disease due to epilepsy is comparable to that of lung cancer in men and breast cancer in women. The current proposal directly deals with the following NIH benchmarks: 1) Understand epileptogenic processes associated with acquired forms of the epilepsies, including those associated with traumatic brain injury, stroke, brain tumor, infections, neurodegeneration, or other insults to the brain. 2) Identify biomarkers that will aid in identifying, predicting, and monitoring epileptogenesis and disease progression, including markers early after injury/insult that identifies those people at rik for epilepsy. In our previous research we've discovered pathological high frequency oscillations (pHFOs) in animal models of chronic epilepsy and patients with temporal lobe epilepsy. These data are confirmed in many other laboratories and now pHFOs are used in patients to help localize the seizure onset zone. It has become evident that epilepsy is a network phenomenon and even focal epilepsy is associated with abnormal changes in connectivity between multiple brain areas. Our understanding of functioning of these networks is limited and approaches are not well developed. In this proposal we are investigating properties of networks in normal conditions and during epileptogenesis in 2 animal models of chronic epilepsy: neocortical and hippocampal. Neocortex is the brain area frequently affected by traumatic injury or/and stroke, and hippocampus is a brain area that reveals cell death in multiple types of epilepsy. We are applying a new approach to study functional connectivity between multiple brain areas by estimating functional relationships of local field potentials in the gamma frequency band. We will identify functional connections that are altered after epileptogenic injury in animals that later develop epilepsy and compare them with those in animals that do not develop epilepsy. We will further investigate properties of normal and pathological functional connections using electrophysiological and pharmacological approaches. Taking into account the spatial limitations of electrophysiological approaches, we are planning to carry out parallel electrophysiological and magnetic resonance imaging experiments, which we believe will yield important complementary data for understanding the properties of normal and pathological networks. Completion of this study will further improve our understanding of mechanisms of epileptogenesis and provide new approaches for treatment of epilepsy.